KR100603974B1 - Method for preparing nano-scale or amorphous particle using solid fat as a solvent - Google Patents

Abstract

The present invention relates to a method for producing nanoscale or amorphous particles using solid lipids, and more particularly, using active lipids as solid solvents at room temperature, which is useful for pharmaceuticals, cosmetics, and functional foods. A method for producing nanoscale or amorphous particles.

Solid lipids, active materials, nano-levels, amorphous, particles, supercritical fluids

Description

Method for preparing nano-level or amorphous particles using solid lipid as solvent {METHOD FOR PREPARING NANO-SCALE OR AMORPHOUS PARTICLE USING SOLID FAT AS A SOLVENT}

The present invention relates to a method for producing nanoscale or amorphous particles using solid lipids, and more particularly, using active lipids as solid solvents at room temperature, which is useful for pharmaceuticals, cosmetics, and functional foods. A method for producing nanoscale or amorphous particles.

Techniques for quickly and effectively producing particles that are very small and of constant size are required in many industries. Small particles of constant size have a number of advantages, and among them, the flowability is good and there is little variation in particle interaction, which is very useful industrially. For example, in the pharmaceutical industry, the size of therapeutic particles is a very important factor in the rate of degradation, biological capacity, formulation, etc. The smaller the deviation in the interaction between the therapeutic particles, the better the overall stability of the therapeutic agent. You lose.

In medicine, the size of the therapeutic agent particles as nanoparticles has the following advantages. First, in the case of a drug having a low absorption rate in the intestine upon oral administration, more particles can be absorbed than large ones, and consequently, increase the biological efficiency of the therapeutic agent. In addition, it is possible to vary the form of the therapeutic formulation, such as to be able to administer to the patient inhaled the drug that was available only by oral administration. In addition, the release rate of the therapeutic agent is a very important factor in the formulation of the sustained release therapeutic agent. If the particle size of the therapeutic agent is nanoparticles, the release rate of the therapeutic agent becomes more predictable as the size becomes relatively uniform, which is more effective. Therapeutic agents can be prepared.

As mentioned above, since uniform nanoparticles have several advantages, various attempts have been made to make active materials into nanoparticles. Traditionally, mechanical methods such as crushing, grinding, milling, etc. have been used to make relatively large particles relatively small. Recently, in the pharmaceutical industry, a method of crushing a large amount of therapeutic drug into a size range suitable for medical use using an air-jet mill is generally used. However, by such a mechanical method, there is a fear of contamination, and the size of the particles is limited to a few tens of micrometers.

U. S. Patent No. 5,145, 684 discloses a method for producing particles of several hundred nanometers in size by grinding poorly soluble drugs using wet milling in the presence of a surfactant. To use this technique, the drug must be made into particles having a size of 100 micrometers or less using conventional grinding methods. In this case, the time required to produce the particle size in the targeted range depends on the mechanical device used, which takes five days or more, using a ball mill. Using a high shear media mill can be made within one day. However, when a high shear media mill is used, the corrosion of grinding media and grinding vessels is very high and contamination is a concern. In addition, since the nanoparticles obtained in this method are liquid, they must be spray dried or lyophilized to produce a powder. However, due to mutual coagulation between the particles during these processes, it is difficult to disperse the obtained powder into particles of substantially nanometer size when dispersed again in the liquid. In order to solve this problem, U.S. Patent No. 5,302,401 describes an anti-agglomeration agent during lyophilization. In addition, US Pat. No. 6,592,903 B2 describes stabilizers, surfactants and anti-agglomeration agents in spray drying. US 2003/0185869 A1 describes an example in which wet milling is applied to various poorly soluble drugs using lysozyme as an interfacial stabilizer. However, in this case, since the interfacial stabilizer is a protein, there are many restrictions on drying, and therefore only the preparation of the liquid form is described.

Another traditional method is a recrystallization method in which microparticles of the active material are made by changing the environment of a solution in which the active material is dissolved to precipitate or crystallize the solute. There are two methods of this recrystallization. One is to dissolve the therapeutic agent in a suitable solvent, and then to lower the temperature to change the solubility of the therapeutic agent to precipitate the particles. The other is an antisolvent in the solvent in which the therapeutic agent is dissolved. (Antisolvent) is added to lower the solvent so that the particles are precipitated. However, these recrystallization methods require the use of organic solvents, which are mostly harmful to the human body, and also frequently precipitate the particles together during the drying in the wet state after filtering the precipitated particles. The particle size may not be constant.

U.S. Patent No. 2003/0104068 A1 describes a method of preparing a fine powder by dissolving a polymer in an organic solvent, dissolving or dispersing a protein drug therein, rapidly cooling to an ultra-low temperature, and solidifying it by lyophilization. However, in this case, there is a concern that the protein drug may be denatured by contact with the organic solvent, and also there are many problems in the economics of the process because it undergoes a process of rapid cooling and lyophilization.

In addition, there are methods for reducing the size of particles using emulsification. This method is widely used in the field of cosmetics, in which poorly soluble substances are dissolved by applying heat or dissolved using an organic solvent, and then added to an aqueous solution in which the surfactant is dissolved, followed by high speed stirring or dispersion using ultrasonic waves. This is a method for producing fine particles. However, in this case, in order to prepare the fine particles into a powder, water must be removed, and various restrictions follow in the process. In addition, when the organic solvent is used to dissolve the poorly soluble substance, there is always a concern about the remaining of the organic solvent harmful to the human body.

US 2004/0067251 A1 discloses a method for preparing microparticles by dissolving an active substance in an organic solvent and spraying it in an aqueous solution in which a surfactant is dissolved. In this method, not only organic solvents are used but also the prepared particles are present in an aqueous solution. Therefore, in order to prepare powders, the water used as a solvent must be dried. During the drying process, the particles are aggregated and redispersed. The particles are difficult to redisperse into nanoscale particles.

In recent years, there have been many attempts to produce amorphous or nanoparticles using supercritical fluids. Supercritical fluids are fluids that exist at temperatures and pressures above the critical temperature and pressure, and carbon dioxide is generally used. As one of methods for preparing nanoparticles using a supercritical fluid, a rapid expansion of supercritical solution (RESS) is known (Tom et al. (1991) Biotechnol.Prog. 7 (5) . US Pat. No. 6,316,030 B1; US Pat. No. 6,352,737 B1, US Pat. No. 6,368,620 B2). According to this method, the target solute is first dissolved in the supercritical fluid, and then the supercritical fluid solution is rapidly injected through the nozzle in a relatively low pressure environment. The density of the supercritical fluid is then drastically lowered, with the result that the dissolving ability of the supercritical fluid to the solute rapidly drops, so that the solutes are formed into very small particles or crystals.

Another method using supercritical fluids is gas-antisolvent recrystallization (GAS) (Debenedetti et al. (1993 ) J. Control. Release 24: 27-44; WO 00/37169). . According to this method, a solution prepared by dissolving a therapeutic agent in a conventional organic solvent is sprayed through a nozzle into a supercritical fluid which acts as an antisolvent. Then, the solution and the supercritical fluid are brought into contact with each other, which causes rapid volume expansion. As a result, the density and dissolving power of the solvent are reduced, resulting in a supersaturated state, so that the solute forms a nucleus or particles.

In addition, US Pat. No. 6,630,121 describes a method of obtaining fine powder by nebulization of a solution in which an active substance is dissolved into fine particles using a supercritical fluid and drying it using a dry gas. This method can be used regardless of the solubility of the active substance in the supercritical fluid. Meanwhile, WO 02/38127 A2 describes a method of coating the resulting micromaterial with an additive such as a polymer while making the active material into a micromaterial using a Solution Enhanced Dispersion by Supercritical fluids (SEDS) method. In addition, U. S. Patent No. 6,596, 206 B2 describes a technique for dissolving an active substance in an organic solvent and applying ultrasonic waves to the solution to spray the supercritical fluid in the form of microparticles so that the active substance is made into microparticles. have.

While these prior arts present methods for producing very small particles with a relatively constant size, there are also various problems.

The first problem exists in the tubes and nozzles that deliver the solution. In general, in the method for producing fine particles using a supercritical fluid, the size of the generated particles is determined by the size of the nozzle diameter, and thus the diameter of the nozzle must be very small and precise. However, as the diameter of the nozzle changes as the number of times of use of the nozzle increases, the size of the particles produced is not uniform over time. In addition, since the nozzle having a very fine diameter must be used for the production of the fine particles, clogging of the nozzle occurs frequently, while the nozzle is clogged and drilled, the particles staying in the tube frequently occur.

The second problem is that the solutes available and the types of solvents available are extremely limited. The RESS method can be used only when the applicable solutes are well dissolved in the supercritical fluid. Of course, the solubility may be increased by using a cosolvent depending on the solute. However, when the amount of the cosolvent is increased, crystal growth may occur due to the remaining solvent after particle formation. Becomes difficult. In addition, the GAS method requires careful selection of the solvent. When the solute-solvent is in contact with the supercritical fluid, it must be rapidly diffused into the supercritical fluid to produce microparticles, and the solvent remaining in the particle during filtration must be minimized to prevent the growth of the particles. In addition, the GAS method requires a special filtration device for filtering the produced microparticles from the solvent.

The third problem is that when the nano-sized particles are prepared using the supercritical fluid by conventional methods, there are many limitations in preparing them on a commercial scale. For commercial use of the RESS method, solutes must be very well soluble in supercritical fluids, with only a few of these materials. In addition, when a single material is made into nano-sized micromaterials, aggregation of particles occurs. Therefore, the anti-aggregation materials such as emulsifiers, cellulose or lipids must be dissolved together to prepare the mixture into nano-sized microparticles. Most of the inhibitors are insoluble in carbon dioxide, the main supercritical fluid. In addition, when preparing nano-sized microparticles using the GAS method, the solution in which the solutes are dissolved must be pushed into the reactor in which the supercritical fluid is present. At this time, the injection speed is very slow to produce particles of uniform size. It is difficult to do, and if the injection speed is increased, the particle size is uneven and there is a lot of filtration problems. In addition, since the solubility of the solute in the solvent and the solubility of the anti-agglomerating agent added together to prevent the aggregation of the particles are different, particles of a composition ratio different from the composition ratio originally intended to be produced may be produced.

The present invention is to solve the problems of the prior art as described above, an object of the present invention, in preparing nano-sized particles using a supercritical fluid, after preparing a mixture comprising the active material and a solid lipid It is to provide a method for producing nano-level or amorphous particles of the active material, by removing the solid lipid from it using a supercritical fluid, which can be prepared as nano-particles or amorphous microparticles.

According to the present invention, (1) preparing a mixture comprising an active substance and a solid lipid, and (2) putting a supercritical fluid gas into a mixture comprising the active substance and a solid lipid at a pressure equal to or greater than the supercritical pressure. After pressurizing, the solid lipid is discharged together with a supercritical fluid gas, thereby removing the solid lipid from the mixture, thereby providing a nano-level or amorphous particle of the active material.

In one preferred embodiment of the present invention, the step (1) is a step of adding the active material, solid lipids and optionally a surfactant to the reactor, and uniformly melt mixed.

In another preferred embodiment of the present invention, the step (1) comprises the steps of adding the active material, the solid phase lipid and optionally the surfactant to the reactor, and homogeneously melt mixing; It is rapidly cooled to solidify; Powdering the solidified mixture; To the obtained powder, a surfactant and / or a flocculant other than the surfactant or an aqueous solution thereof is added and mixed uniformly; This is a step of drying at room temperature.

In another preferred embodiment of the present invention, the step (1) comprises the steps of adding a surfactant and a solid lipid to the reactor, and homogeneously melt mixing; It is rapidly cooled to solidify; Powdering the solidified mixture; To the obtained powder, a surfactant and / or an aggregation agent other than the surfactant or an aqueous solution thereof are added together with the active substance and mixed uniformly; This is a step of drying at room temperature.

In another preferred embodiment of the present invention, the step (1), the active material, the solid lipid and optionally the surfactant is added to the reactor, the supercritical fluid gas is further added to the subcritical state or supercritical state Making and then heating to melt and mix the mixture.

In another preferred embodiment of the present invention, in the step (1), the active material, the solid lipid and optionally the surfactant is added to the reactor, and the supercritical fluid gas is added thereto to pressurize at a pressure equal to or higher than the supercritical pressure. After melting, the molten mixture is sprayed at atmospheric pressure.

In another preferred embodiment of the present invention, in the step (1), the active material, the solid lipid and optionally the surfactant is added to the reactor, and the supercritical fluid gas is added thereto to pressurize at a pressure equal to or higher than the supercritical pressure. Melt and then powder the molten mixture by spraying at atmospheric pressure; To this powdered mixture, a surfactant and / or a flocculant other than the surfactant or an aqueous solution thereof is added and mixed uniformly; This is a step of drying at room temperature.

In the present specification, the term "supercritical fluid gas" is an inert gas that is not reactive, such as carbon dioxide gas or nitrogen gas, and supercritical fluid at a specific temperature and a specific pressure, that is, supercritical temperature and supercritical pressure. A gas that can be a fluid.

In addition, in the present specification, the term "supercritical pressure" refers to a specific pressure at which the supercritical fluid gas can become a supercritical fluid under a pressure higher than the pressure.

In the method for producing nanoscale or amorphous particles (hereinafter referred to as "nanoparticles") of the present invention, the active substance may be, for example, an organic compound or an organic compound exhibiting physiological activity in pharmaceuticals, functional foods, cosmetics, etc. Metal compounds, natural extracts, proteins, polysaccharides, and the like can be used, and there are no particular limitations on the electrical form, such as properties at room temperature, such as solid or liquid phase, and neutral or ionic.

In the present specification, the term "nanoparticles" refers to particles having a size of 90% or more of 5 µm or less, preferably 2 µm or less, more preferably 1 µm or less, even more preferably 0.5 µm or less. it means.

In the method for preparing nanoparticles of the present invention, the solid lipid is maintained at room temperature, that is, at a temperature of 30 ° C. or lower, and the melting point is relatively low at 40 to 150 ° C., so that it is easily dissolved by heating and is a solvent for the active material. Lipids with high solubility in supercritical fluids are used. Examples of such solid lipids include saturated fatty acids having 10 to 22 carbon atoms, ester compounds and alcohol compounds thereof, mono- or diglyceride compounds having saturated fatty acid groups having 10 to 22 carbon atoms, hydrocarbons having 16 or more carbon atoms, and the like. The triglyceride compound of ˜22 can also be used in the present invention by reducing fatty acids to solidify it.

In the nanoparticle manufacturing method of the present invention, the active material as a single component may be prepared in nano-sized particles, in some cases may be further used to prevent the aggregation of the prepared nano-sized particles to further prevent aggregation. have. Such anticoagulants can be broadly classified into surfactants and anticoagulants other than surfactants. As the surfactant, for example, various synthetic and natural surfactants, lipids, polymers, and the like can be used. As the anti-aggregation agents other than the surfactant, monosaccharides, polysaccharides, dietary fibers, gums and proteins can be used. Phospholipids such as lecithin, lyso lecithin, phosphatidyl choline, phosphatidyl ethylamine and the like may be generally classified as lipids, but are classified as surfactants in the present invention. In general, surfactants are classified into hydrophilic and lipophilic according to affinity for water, and are classified into hydrophilic-lipophilic balance (HLB) values. It can also be divided into cationic, anionic, neutral and positive, depending on the form of the functional group. Surfactants that can be used in the present invention are not particularly limited as long as they prevent aggregation of the active substance, are well soluble in the solid lipid, and are not easily removed by a supercritical fluid.

In addition, in the method for producing nanoparticles of the present invention, when the active substance and the surfactant cannot be sufficiently dissolved with only the solid lipid, alcohol may be further used as a cosolvent. The alcohol is preferably a lower alcohol having 2 to 6 carbon atoms, and ethanol is most preferred.

Hereinafter, the nanoparticle manufacturing method of the present invention will be described in more detail at each step.

In the method for producing nanoparticles of the present invention, in step (1), a mixture including the active substance and a solid lipid is prepared. This will be described in more detail as follows.

In a preferred embodiment of the present invention, 0.1 to 1000 parts by weight of the active material and solid lipid per 1 part by weight of the active material are added together to the reactor. At this time, if necessary, a mixture of 0.001 to 10 parts by weight of surfactant or 0.001 to 10 parts by weight of lower alcohol or 0.001 to 10 parts by weight of surfactant and 0.001 to 10 parts by weight of lower alcohol is optionally added to 1 part by weight of the active substance. Can be added to the reactor.

In the above, the selectively added surfactant has a relatively high solubility with respect to the solid lipid, and when dissolved in the solid lipid with the active material or in the solid lipid containing a lower alcohol described later, forms a uniform solution. You should be able to. In addition, the surfactant may be selected differently depending on the nature of the active material and the purpose or use of the nanoparticles to be produced. In the case where the nanoparticles to be prepared are dispersed and used in water, a surfactant having a high HLB value is preferably selected, and a surfactant having a relatively low HLB value is selected in order to increase the body absorption rate. It is preferable.

As described above, the active substance and the solid lipid are added to the reactor, and if necessary, a surfactant or a lower alcohol or a mixture of the surfactant and the lower alcohol is further added to the reactor, and then slowly heated to dissolve.

As the temperature in the reactor rises, the solid lipid melts, and the active material, surfactant, and the like dissolve therein. The temperature is raised to a temperature that forms a uniform solution. At this time, it is preferable to carry out the stirring from the time point at which the stirring becomes possible, in order to make the mixture solution more uniform and to shorten the working time. The time point at which stirring is possible depends on the type of active substance, the surfactant and the solid phase lipid, and anyone in this field can select the time point at the site.

In addition, in another preferred embodiment of the present invention, as described above, the active substance, the solid lipid and optionally the surfactant are introduced into the reactor and uniformly melt mixed, and then further rapidly cooled to solidify and solidify. The mixture is powdered, and a mixture comprising an active substance and a solid lipid is prepared by adding a surfactant and / or a flocculant other than the surfactant or an aqueous solution thereof and uniformly mixing the same, and drying it at room temperature. . The drying process above is not limited to any particular method, but must be carried out at a temperature below the melting point of the lipid used.

Further, in another preferred embodiment of the present invention, when the active substance is temperature sensitive or water soluble, such as a protein or polysaccharide, the surfactant and the solid phase lipid are first introduced into the reactor and uniformly melt mixed, and this is After rapidly cooling to solidify and powdering the solidified mixture, the obtained powder is mixed with an active substance and a surfactant and / or a flocculant other than a surfactant or an aqueous solution thereof, mixed very uniformly, and dried at room temperature. To prepare a mixture comprising the active substance and a solid lipid. The drying process above is not limited to any particular method, but must be carried out at a temperature below the melting point of the lipid used.

When solidifying by rapid cooling, it is preferable that the molten mixture solution is rapidly cooled and solidified to 10 ° C or lower. If cooling is carried out slowly, crystal growth may occur between the active materials, which may make it difficult to achieve nanoparticles of the active material, and may also widen the distribution of the resulting particles.

Solids obtained by rapid cooling are ground by conventional grinding methods, i.e. by dry milling. The finer the size of the pulverized particles, i.e., the larger the surface area of the particles, the better the subsequent processes such as the lipid removal process. The size of the ground particles is preferably within 100 micrometers, but is not limited thereto.

In another preferred embodiment of the present invention, the active material, the solid lipid and optionally the surfactant are added to the reactor, and a supercritical fluid gas (for example, CO ₂ gas) is further added to the subcritical state or It is made into a supercritical state and then heated to dissolve the mixture to prepare a mixture comprising the active substance and solid lipids.

In another preferred embodiment of the present invention, the active material, the solid lipid and optionally the surfactant are added to the reactor, the supercritical fluid gas is added thereto, pressurized to a pressure equal to or greater than the supercritical pressure, and then melted. Spraying the mixture to atmospheric pressure produces a mixture comprising the active substance and solid lipids.

In another preferred embodiment of the present invention, the active material, the solid lipid and optionally the surfactant are added to the reactor, supercritical fluid gas is added thereto and pressurized to a pressure equal to or greater than the supercritical pressure, and then the molten mixture is pressed. After spraying to atmospheric pressure and powdering, the powdered mixture is uniformly mixed with a surfactant and / or a flocculant other than the surfactant or an aqueous solution thereof, and is dried at room temperature to contain the active substance and the solid lipid. To prepare a mixture. The drying process above is not limited to any particular method, but must be carried out at a temperature below the melting point of the lipid used.

In the step (1) of the present invention, in the case of using a supercritical fluid, when all of the mixture is melted and mixed uniformly, a supercritical fluid gas (for example, CO ₂ ) is gradually introduced into the reactor to become a supercritical fluid ( Supercritical pressure; 70 atm for CO ₂ ). The pressure in the reactor at this time is determined depending on the size of the reactor and the amount of the mixture, but is generally preferably 50 to 200 atmospheres. The temperature at this time should just be a temperature at which a mixture solution can have sufficient fluidity so that stirring can be maintained smoothly.

When the pressure in the reactor rises and the pressure of the supercritical fluid gas reaches the supercritical fluid, it is preferable to stir for 10 minutes or more in such a state so that the supercritical fluid is sufficiently infiltrated into the mixture solution.

Once further agitation is complete, the outlet is opened to the fullest extent with a slower addition of the supercritical fluid gas, which is then injected into another reactor at atmospheric pressure. At this time, as the supercritical fluid vaporizes instantaneously, the surrounding temperature is rapidly cooled, which causes the mixture solution to solidify instantaneously. As the mixture solution solidifies in this instant, it is impossible to have the energy and time necessary for crystal growth, thereby obtaining a solid having a very uniform mixture of solutes such as active substances and surfactants and solid lipids into very fine particles. Can be. In the solid obtained in this way, particles of very fine active material are uniformly dispersed in the size of the particles at the nano level. In addition, since the surfactant is also very uniformly mixed with the active substance, the dispersibility and stability of the final produced fine particles are greatly improved.

The present invention is characterized by making the particles of the active substance present in the solid fine and uniform, so that the particle size of the solid itself needs to be specially adjusted within a range that does not interfere with subsequent workability. none. Therefore, it is not necessary to reduce the diameter of the injection nozzle or to adjust the injection speed in order to control the particle size of the solid produced by injection at atmospheric pressure, and there is no need to worry about deformation or clogging of the injection nozzle.

At the time of spraying to atmospheric pressure, it is preferable to install a conical support plate at a certain distance from the ejection outlet so as to solidify the ejected fluid into a finer powder form. This is because the smaller the solids are produced in the smaller powder, the easier it is to remove the solid lipid in the supercritical fluid in the next step.

In a preferred embodiment of the present invention, to the mixed powder obtained by using a supercritical fluid or a grinder, a flocculant or an aqueous solution other than the surfactant and / or the surfactant, or the active substance is a protein or When temperature sensitive or water soluble, such as polysaccharides, it is possible to add surfactants and / or anti-agglomerates or aqueous solutions thereof together with the actives, and the resulting mixture can be mixed very uniformly using a common mixer. Can be. At this time, 0.001-10 weight part of antifouling agents other than surfactant is added with respect to 1 weight part of active substances as needed. When an aqueous solution is added, the properties of the mixture produced vary depending on the amount of water used, the type of surfactant and the anti-agglomerating agent, but the amount of water added is generally 30% (w / w) of the amount of lipid used Within this range, a powdery phase is easily formed. The amount of water to be added is not particularly limited as long as it is sufficient to disperse the water-soluble raw materials to be added. If water is used in excess of 40% (w / w) of lipids, the mixture is in the form of dough or paste, which can be easily dried by various conventional methods at room temperature. The drying process is not limited to any particular method, but must be carried out at a temperature below the melting point of the lipid used. In addition, the finer the particles of the powder used, the easier it is to remove moisture by the traditional vacuum drying process, it can be easily seen by those skilled in the art. After the removal of water, the content of residual moisture relative to lipids is preferably less than 30%.

In the method for producing nanoparticles of the present invention, in step (2), the solid lipid is removed from the mixture including the active substance and the solid lipid using a supercritical fluid. This will be described in more detail as follows.

Supercritical in the reactor, while maintaining the temperature of the reactor containing the mixture obtained in the previous step comprising the step (1) below the melting point of the solid phase lipid present in the mixture, preferably 20 ~ 40 ℃ When the fluid gas is injected and pressurized to 70 to 400 atm, and under this pressure, the supercritical fluid gas is gradually discharged while maintaining the pressure in the reactor by adjusting the carbon dioxide inlet valve and the discharge valve, the solid lipid is a supercritical fluid. It is discharged with the gas to be removed. At this time, if the temperature inside the reactor is too high, the solid lipid melts, and thus, the active material, the surfactant, and the anti-agglomerating agent, which are uniformly distributed in the mixture, grows to crystallization, resulting in uniform nano-level fines. No particles can be obtained. Therefore, the temperature of the reactor is preferably maintained at a temperature below the melting point of the solid lipid present in the mixture, and more preferably 20 to 40 ° C. in consideration of workability.

In addition, the time taken to remove the solid lipid with the supercritical fluid greatly depends on the type and amount of the solid lipid used, and in order to obtain higher purity active substance particles, the solid lipid is removed for as long as possible to remain. It is desirable to minimize the amount of solid phase lipids. Solid lipids preferably used in the present invention are harmless to the human body, and therefore, the amount of residual lipids need not be limited to a specific range. Do. Of course, in the case of using a solid lipid that is also used as a surfactant, such as a mono-, di- or tri-glyceride-based compound, it can be said that the residual amount may be more than 10%.

The solid lipids removed from the mixture as described above can be collected in a separate reactor and continue to be used in the next production process.

Hereinafter, the present invention will be described in detail with reference to the following examples, but the present invention is not limited thereto.

Example 1

2 g of ketoconazole as an active substance and 18 g of cetyl alcohol as a solid lipid were added to a 80 ml internal pressure reactor, and the mixture was slowly heated to start stirring when the temperature in the reactor reached 70 ° C. Heating was continued and when the temperature in the reactor reached 80 ° C., a homogeneous solution of a clear liquid phase was obtained.

Next, a supercritical fluid inlet valve was opened to inject carbon dioxide gas as a supercritical fluid gas to increase the pressure in the reactor. The carbon dioxide gas was continuously added, and the pressure in the reactor reached 120 atm above the supercritical pressure of carbon dioxide. Then, the supercritical fluid inlet valve was closed and further stirred for 20 minutes. After further stirring was completed, the supercritical fluid inlet valve was again opened to slowly inject carbon dioxide gas, and the injection valve connected to the recovery reactor at atmospheric pressure was temporarily opened, and the mixture solution was completely injected into the recovery reactor. At this time, the exhaust valve installed in the recovery reactor was completely opened in order to maintain the recovery reactor at atmospheric pressure. In addition, a conical plate was installed in the front of the injection nozzle so that the solution to be injected can be formed into a finer powder. Even after the injection of the solution was completed, the carbon dioxide gas was further flowed for 10 minutes, and then the supercritical fluid inlet valve and the injection valve were closed.

Next, after injecting carbon dioxide gas into the recovery reactor in which the injected solid powder is present, the pressure in the reactor is about 150 atm, and while the carbon dioxide gas is continuously added, the exhaust valve of the recovery reactor is adjusted to adjust the pressure in the recovery reactor to 100 atm. While maintaining the above constant pressure, by using supercritical fluid gas, cetyl alcohol (cetyl alcohol) used as solid lipid was extracted for 8 hours, thereby obtaining 1.8 g of fine particles of solid powder from which solid lipid was removed. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Mastersizer Microplus), and the results are shown in Table 1.

Example 2

30 g of cetyl alcohol and 2 g of ketoconazole were placed in a 250 ml beaker and heated to 80 ° C. and stirred until the mixture melted completely and became a clear liquid. The mixture is stirred for another 10 minutes to completely dissolve and then uniformly mixed, and the melt is poured into a stainless steel plate cooled to 10 ° C. or lower to quickly solidify, thereby preparing a solid in which the active substance is uniformly distributed as fine particles in lipids. It was. 2 g of sucrose (D-(+)-Sucrose) was added to the solid as a coagulant, and ground to a fine powder using a domestic grinder to obtain a lipid powder. 5.5 g of this lipid powder was placed in a pressure resistant reactor and cetyl alcohol used as a solid lipid was removed in the same manner as in Example 1 to obtain 0.6 g of a mixed powder of ketoconazole and sucrose. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Mastersizer Microplus), and the results are shown in Table 1.

Example 3

20 g of cetyl alcohol and 1 g of ketoconazole as solid lipids were placed in a 250 ml beaker and heated to 80 ° C. until the mixture was completely melted and became a clear liquid. After the mixture is completely dissolved, it is stirred for another 10 minutes to ensure a homogeneous mixing, and the melt is poured into a stainless steel plate cooled to 10 ° C or below to quickly solidify, so that the active material is uniformly distributed as fine particles in lipids. Was prepared. The solid is pulverized into a lipid powder having a size of about 100 μm using a domestic grinder, and a solution obtained by dissolving 1 g of sucrose in 5 ml of water as a coagulant is added to the powder, so that the powder and the sucrose solution are uniformly mixed. Stir well with a spatula to obtain lipid powder to which sucrose was added. This mixture was easily in powder form because of the low water content. 13.5 g of this sucrose-added lipid powder was placed in a pressure-resistant reactor, and cetyl alcohol used as a solid lipid was removed in the same manner as in Example 1 to obtain 0.9 g of a mixed powder of ketoconazole and sucrose. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Mastersizer Microplus), and the results are shown in Table 1.

Example 4

A lipid powder added with sucrose in the same manner as in Example 3, except that a solution obtained by dissolving 2 g of sucrose in 5 ml of water as an anticoagulant was added to 21 g of a lipid powder composed of ketoconazole and cetyl alcohol (1 g and 20 g, respectively). Was prepared. 10.4 g of this lipid powder was placed in a pressure resistant reactor and cetyl alcohol used as a solid lipid was removed in the same manner as in Example 1 to obtain 1.0 g of a mixed powder of ketoconazole and sucrose. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Mastersizer Microplus), and the results are shown in Table 1.

Example 5

A lipid powder added with sucrose in the same manner as in Example 3, except that a solution obtained by dissolving 1 g of sucrose in 8 ml of water as an anticoagulant is added to 21 g of a lipid powder composed of ketoconazole and cetyl alcohol (1 g and 20 g, respectively). Was prepared. 10.0 g of this lipid powder was placed in a pressure resistant reactor and cetyl alcohol used as a solid solvent was removed in the same manner as in Example 1 to obtain 0.4 g of a mixed powder of ketoconazole and sucrose having excellent flowability. This mixed powder adsorbed a considerable amount inside the reactor. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Mastersizer Microplus), and the results are shown in Table 1.

[Table 1] Average particle size of the final powder prepared in Examples 1-5 (㎛)

Raw material (active substance) Example 1 Example 2 Example 3 Example 4 Example 5 Average particle size 10.41 1.79 1.02 1.04 1.10 0.75

Example 6

A solution of 0.1 g of polyvinylpyrrolidone K 30 as a surfactant and 1 g of sucrose as an anticoagulant other than a surfactant was dissolved in 8 ml of water, and 21 g of a lipid powder composed of ketoconazole and cetyl alcohol (1 g and 20 g, respectively). A lipid powder to which polyvinylpyrrolidone and sucrose was added was prepared in the same manner as in Example 3, except for the addition. 10.0 g of this lipid powder was placed in a pressure resistant reactor and cetyl alcohol used as a solid lipid was removed in the same manner as in Example 1 to obtain 0.64 g of a mixed powder of ketoconazole, sucrose and polyvinylpyrrolidone having excellent flowability. . This mixed powder adsorbed a considerable amount inside the reactor. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 7

0.1 g of polyvinylpyrrolidone and 1 g of ketoconazole were dissolved together with 20 g of cetyl alcohol to prepare a lipid powder in which ketoconazole and polyvinylpyrrolidone were uniformly dispersed into fine particles. A sucrose-added lipid powder was prepared in the same manner as in Example 3, except that the solution dissolved in 8 ml was added. 10.0 g of this lipid powder was placed in a pressure resistant reactor and cetyl alcohol used as a solid lipid was removed in the same manner as in Example 1 to obtain 0.62 g of a mixed powder of ketoconazole, sucrose and polyvinylpyrrolidone having excellent flowability. . This mixed powder adsorbed a considerable amount inside the reactor. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 8

0.1 g of polyvinylpyrrolidone and 1 g of ketoconazole were dissolved together with 20 g of cetyl alcohol to prepare a lipid powder in which ketoconazole and polyvinylpyrrolidone were uniformly dispersed into fine particles in the same manner as in Example 3. As a flocculant, a solution of 1 g of sucrose dissolved in 14 ml of water was added and mixed uniformly. The mixture was dried using a vacuum dryer to have a water content of 5% (w / w) or less relative to lipids. 9 g of the thus obtained lipid powder was placed in a pressure-resistant reactor, and lipids were removed in the same manner as in Example 1 to obtain a mixed powder having an excellent flowability of 0.8 g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 9

As a coagulation agent, a solution of 2 g of sucrose in 14 ml of water was added to a lipid powder prepared by dissolving 0.1 g of polyvinylpyrrolidone and 1 g of ketoconazole together with 20 g of cetyl alcohol. The lipid powder to which cross was added was prepared, and lipid was removed from the lipid powder in the same manner as in Example 1 to obtain a mixed powder having very high flowability of 1.1 g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 10

As a coagulation agent, a solution obtained by dissolving 1 g of xylitol in 14 ml of water was added to a lipid powder prepared by dissolving polyvinylpyrrolidone (0.1 g) and ketoconazole (1 g) together with 20 g of cetyl alcohol. A lipid powder to which xylitol was added was prepared by the method. Lipid was removed from the lipid powder in the same manner as in Example 1 to obtain a mixed powder having very good flowability of 0.8 g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 11

A solution of 1 g of xylitol as a coagulant, 0.08 g of sodium dioctyl sulfosuccinate (DOSS) and 0.008 g of sodium dodecylsulfate (SLS) in an additional surfactant was dissolved in 14 ml of water. A lipid powder to which xylitol, DOSS and SLS was added was prepared in the same manner as in Example 8, except that 0.1 g of pyrrolidone and 1 g of ketoconazole were added to a lipid powder prepared by dissolving 20 g of cetyl alcohol. Lipids were removed from 10 g of powder in the same manner as in Example 1 to obtain a mixed powder having a very good flowability of 0.9 g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 12

0.25 g of polyvinylpyrrolidone and 1 g of ketoconazole were dissolved together with 20 g of cetyl alcohol to prepare a powder in which ketoconazole and polyvinylpyrrolidone were uniformly dispersed in lipids as fine particles in the same manner as in Example 2. As an inhibitor, a solution of 1 g of xylitol dissolved in 14 ml of water was added to the powder and mixed uniformly. The mixture was dried using a vacuum dryer to 5% or less of lipid. The powder thus obtained was placed in a pressure resistant reactor, and lipids were removed in the same manner as in Example 1 to obtain a mixed powder having an excellent flowability of 0.88 g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 13

0.25 g of polyvinylpyrrolidone and 1 g of ketoconazole were dissolved together with 20 g of cetyl alcohol, to prepare a lipid powder in which ketoconazole and polyvinylpyrrolidone were uniformly dispersed into fine particles in the same manner as in Example 2. As a flocculant, a solution of 1 g of sucrose dissolved in 14 ml of water was added and uniformly mixed. The mixture was dried using a vacuum dryer so that the moisture content was 5% (w / w) or less relative to the lipid. 9 g of the powder thus obtained was placed in a pressure resistant reactor, and lipids were removed in the same manner as in Example 1 to obtain a mixed powder having very good flowability of 0.87 g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 14

A solution of 1 g of xylitol as an anticoagulant and 0.2 g of DOSS and 0.004 g of SLS as an additional surfactant was dissolved in 14 ml of water, and 0.25 g of polyvinylpyrrolidone and 1 g of ketoconazole were added to a lipid powder prepared by dissolving 20 g of cetyl alcohol. Except for this, a lipid powder to which xylitol, DOSS and SLS was added was prepared in the same manner as in Example 12, and from the 9.06 g of the lipid powder to which polyvinylpyrrolidone and xylitol were added, the lipid was added in the same manner as in Example 1. Was removed to obtain a mixed powder having a very good flowability of 0.96g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 15

0.13 g of sucrose fatty acid ester (Sucrose Fatty Acid Ester) and 1 g of ketoconazole were dissolved together with 20 g of cetyl alcohol, to prepare a lipid powder in which ketoconazole and sucrose fatty acid ester were uniformly dispersed into fine particles in the same manner as in Example 2. A lipid powder to which sucrose was added was prepared in the same manner as in Example 3, except that a solution obtained by dissolving 1 g of sucrose in 9 ml of water was added to the lipid powder as an aggregation agent. 9.0 g of this lipid powder was placed in a pressure resistant reactor and cetyl alcohol used as a solid lipid was removed in the same manner as in Example 1 to obtain 1.18 g of a mixed powder of sucrose fatty acid ester, sucrose and ketoconazole having excellent flowability. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 16

0.25 g of sucrose fatty acid ester and 1 g of ketoconazole are dissolved together with 20 g of cetyl alcohol, to prepare a lipid powder in which ketoconazole and sucrose fatty acid ester are uniformly dispersed into fine particles in the same manner as in Example 2, and an anti-agglomeration agent in the lipid powder. A solution of 1 g of sucrose dissolved in 14 ml of water was added and mixed uniformly, and the mixture was dried using a vacuum dryer so that the moisture content was 5% (w / w) or less relative to the lipid. 10 g of the powder thus obtained was placed in a pressure resistant reactor, and lipids were removed in the same manner as in Example 1 to obtain 0.89 g of a mixed powder having excellent flowability. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 17

0.25 g of sucrose fatty acid ester and 1 g of ketoconazole were dissolved together with 20 g of cetyl alcohol, to prepare a lipid powder in which ketoconazole and sucrose fatty acid ester were uniformly dispersed into fine particles in the same manner as in Example 2. A solution of 1 g of xylitol dissolved in 14 ml of water was added and mixed uniformly. The mixture was dried using a vacuum dryer so as to have a water content of 5% (w / w) or less relative to lipids. 10 g of the powder thus obtained was placed in a pressure resistant reactor, and lipids were removed in the same manner as in Example 1 to obtain 0.87 g of a mixed powder having excellent flowability. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 18

0.25 g of polyvinylpyrrolidone and 1 g of lovastatin were dissolved together with 20 g of cetyl alcohol, to prepare a lipid powder in which lovastatin and polyvinylpyrrolidone were uniformly dispersed into fine particles in the same manner as in Example 2. A solution in which 1 g of xylitol was dissolved in 14 ml of water as a coagulant was added to the lipid powder and mixed uniformly. 10 g of the powder thus obtained was placed in a pressure resistant reactor, and lipids were removed in the same manner as in Example 1 to obtain a mixed powder having very good flowability of 0.85 g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 19

0.25 g of polyvinylpyrrolidone and 1 g of paclitaxel were dissolved together with 20 g of cetyl alcohol, and lipid powder in which paclitaxel and polyvinylpyrrolidone were uniformly dispersed into fine particles was prepared in the same manner as in Example 2. To the powder was added, a solution in which 1 g of xylitol was dissolved in 14 ml of water as a coagulant was added and mixed uniformly. It was. 10 g of the powder thus obtained was placed in a pressure resistant reactor, and lipids were removed in the same manner as in Example 1 to obtain a mixed powder having an excellent flowability of 1.02 g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

Example 20

0.25 g of polyvinylpyrrolidone and 1 g of itraconazole were dissolved together with 20 g of cetyl alcohol, to prepare a lipid powder in which itraconazole and polyvinylpyrrolidone were uniformly dispersed into fine particles in the same manner as in Example 2. A solution of 1 g of xylitol dissolved in 14 ml of water as a coagulant was added to the powder, and the mixture was uniformly mixed. The mixture was dried using a vacuum dryer so that the water content was 5% (w / w) or less relative to lipid. 10 g of the powder thus obtained was placed in a pressure resistant reactor, and lipids were removed in the same manner as in Example 1 to obtain a mixed powder having very good flowability of 1.05 g. The obtained mixed powder was dispersed in distilled water, and the particle size was measured using a particle size analyzer (Horiba LA910S), and the results are shown in Table 2.

TABLE 2 Particle size distribution of final powders prepared in Examples 6-20 (μm)

Example D50 D70 D90 Average 6 0.4796 0.6785 1.0873 0.5941 7 0.4678 0.6346 1.1100 0.7205 8 0.4787 0.6983 1.4772 0.9289 9 0.5114 0.7515 1.3731 0.7695 10 0.5045 0.7341 1.3185 0.7565 11 0.5966 0.8978 1.4914 0.8793 12 0.4528 0.6064 1.0082 0.6542 13 0.4630 0.6223 1.0392 0.6603 14 0.5061 0.6921 1.0850 0.6191 15 0.5243 0.7500 1.2812 0.9024 16 0.5278 0.8728 1.6520 0.8335 17 0.5702 0.8982 1.5235 0.7759 18 0.4452 0.6164 1.0012 0.5954 19 0.4764 0.6074 1.0068 0.6052 20 0.5164 0.6257 1.1200 0.7021

According to the present invention, by removing a solid lipid from a mixture comprising an active substance and a solid lipid using a supercritical fluid, it is possible to prepare nanoparticle-level or amorphous active substance microparticles, prepared according to the present invention. Nanoparticles have excellent dispersibility, absorbency, and physiological activity, and thus are suitable for use in medicines, functional foods, general foods, and cosmetics.

Claims (36)

(1) preparing a mixture comprising the active substance and the solid lipid and (2) adding a supercritical fluid gas to the mixture comprising the active substance and the solid lipid and pressurizing it to a pressure equal to or greater than the supercritical pressure, and then Removing the solid lipid from the mixture by discharging the solid lipid together with a critical fluid gas. According to claim 1, wherein step (1), the active material, a solid phase lipid and optionally a surfactant is added to the reactor, the method for producing nano-particles of the active material, characterized in that the melt mixing uniformly . The method of claim 1, wherein the step (1) comprises: adding an active substance, a solid lipid, and optionally a surfactant to the reactor, and homogeneously melt mixing them; It is rapidly cooled to solidify; Powdering the solidified mixture; To the obtained powder, a surfactant and / or a flocculant other than the surfactant or an aqueous solution thereof is added and mixed uniformly; Nano-level particle production method of the active material, characterized in that the step of drying at room temperature. The method of claim 1, wherein the step (1) comprises: adding a surfactant and a solid lipid to the reactor and uniformly melt-mixing it; It is rapidly cooled to solidify; Powdering the solidified mixture; To the obtained powder, a surfactant and / or an aggregation agent other than the surfactant or an aqueous solution thereof are added together with the active substance and mixed uniformly; Nano-level particle production method of the active material, characterized in that the step of drying at room temperature. The method of claim 1, wherein the step (1) comprises adding an active substance, a solid lipid, and optionally a surfactant to the reactor, and further adding a supercritical fluid gas to a subcritical state or a supercritical state. Method of producing a nano-level particles of the active material, characterized in that the step of melting and mixing the mixture by heating. According to claim 1, wherein the step (1), the active material, the solid lipid and optionally the surfactant is added to the reactor, the supercritical fluid gas is added to the pressurized to a pressure equal to or more than the supercritical pressure to melt, and then Method of producing a nano-level particles of the active material, characterized in that the step of spraying the molten mixture to atmospheric pressure. According to claim 1, wherein the step (1), the active material, the solid lipid and optionally the surfactant is added to the reactor, the supercritical fluid gas is added to the pressurized to a pressure equal to or more than the supercritical pressure to melt, and then Powdered by spraying the molten mixture to atmospheric pressure; To this powdered mixture, a surfactant and / or a flocculant other than the surfactant or an aqueous solution thereof is added and mixed uniformly; Nano-level particle production method of the active material, characterized in that the step of drying at room temperature. The method according to any one of claims 1 to 7, wherein the active material is an organic compound, an organometallic compound, a natural extract, a protein, or a polysaccharide, which exhibits physiological activity. . The preparation of the nano-level particles of the active substance according to any one of claims 1 to 7, wherein the solid phase lipid is a lipid having a solid phase at a temperature of 30 ° C. or lower and a melting point of 40 ° C. to 150 ° C. Way. 10. The method of claim 9, wherein the solid lipid is a C10-22 saturated fatty acid and its ester compound and its alcohol compound, a mono- or di-glyceride compound having a C10-22 saturated fatty acid group, a hydrocarbon having 16 or more carbon atoms A method for producing nanoscale particles of an active substance, characterized in that it is a mixture of one or more compounds selected from the group consisting of fatty acid reducing compounds of the triglyceride compounds of 10 to 22. 8. The mixture according to any one of claims 1 to 7, wherein the mixture prepared in step (1) comprises a synthetic surfactant, a natural surfactant, a lipid, a polymer, a monosaccharide, a polysaccharide, a dietary fiber, a gum and a protein. Nano-level particle production method of the active material, characterized in that it further comprises one or more materials selected from. The preparation of the nano-level particles of the active material according to any one of claims 2 to 7, wherein the surfactant is at least one selected from the group consisting of synthetic surfactants, natural surfactants, lipids and polymers. Way. 8. The active substance according to any one of claims 3, 4 and 7, wherein the anti-flocculation agent other than the surfactant is selected from the group consisting of monosaccharides, polysaccharides, dietary fibers, gums and proteins. Nano-level particle production method. The method of producing nanoparticles according to any one of claims 1 to 7, wherein a co-solvent is further used in the step (1). 15. The method of claim 14, wherein the cosolvent is an alcohol having 2 to 6 carbon atoms. The activity according to any one of claims 1 to 7, wherein the temperature in the reactor in step (2) is a temperature below the melting point of the solid lipid contained in the mixture obtained in step (1). Method for producing nanoscale particles of materials. 8. The method of claim 1, wherein the temperature in the reactor in step (2) is 20 to 40 ° C. 9. The method according to any one of claims 1 to 7, wherein in step (2), supercritical fluid gas is added to a mixture comprising the active substance and the solid lipid to remove the solid lipid under 70 to 400 atmospheres. Nano-level particle production method of the active material, characterized in that. (1) preparing a mixture comprising the active substance and the solid lipid and (2) adding a supercritical fluid gas to the mixture comprising the active substance and the solid lipid and pressurizing it to a pressure equal to or greater than the supercritical pressure, and then Removing the solid lipid from the mixture by discharging the solid lipid together with a critical fluid gas. 20. The method of claim 19, wherein the step (1) comprises the step of adding the active material, the solid phase lipid and optionally the surfactant to the reactor, and uniformly melt-mixing the active material. 20. The method of claim 19, wherein step (1) comprises: introducing an active substance, a solid lipid, and optionally a surfactant into the reactor, and homogeneously melt mixing them; It is rapidly cooled to solidify; Powdering the solidified mixture; To the obtained powder, a surfactant and / or a flocculant other than the surfactant or an aqueous solution thereof is added and mixed uniformly; Method for producing amorphous particles of the active material, characterized in that the step of drying at room temperature. 20. The method of claim 19, wherein step (1) comprises: adding a surfactant and a solid lipid to the reactor, and homogeneously melt mixing them; It is rapidly cooled to solidify; Powdering the solidified mixture; To the obtained powder, a surfactant and / or an aggregation agent other than the surfactant or an aqueous solution thereof are added together with the active substance and mixed uniformly; Method for producing amorphous particles of the active material, characterized in that the step of drying at room temperature. 20. The method according to claim 19, wherein the step (1) comprises adding an active substance, a solid lipid, and optionally a surfactant to the reactor, and further adding a supercritical fluid gas to subcritical or supercritical state. Method for producing amorphous particles of the active material, characterized in that the step of melting and mixing the mixture by heating. 20. The method of claim 19, wherein the step (1) comprises adding an active substance, a solid lipid, and optionally a surfactant to a reactor, adding a supercritical fluid gas to the reactor, and pressing the melt to a pressure equal to or greater than the supercritical pressure, and Method for producing amorphous particles of the active material, characterized in that the step of spraying the molten mixture to atmospheric pressure. 20. The method of claim 19, wherein the step (1) comprises adding an active substance, a solid lipid, and optionally a surfactant to a reactor, adding a supercritical fluid gas to the reactor, and pressing the melt to a pressure equal to or greater than the supercritical pressure, and Powdered by spraying the molten mixture to atmospheric pressure; To this powdered mixture, a surfactant and / or a flocculant other than the surfactant or an aqueous solution thereof is added and mixed uniformly; Method for producing amorphous particles of the active material, characterized in that the step of drying at room temperature. The method according to any one of claims 19 to 25, wherein the active substance is an organic compound, an organometallic compound, a natural extract, a protein, or a polysaccharide which exhibits physiological activity. The method of claim 19, wherein the solid lipid is a lipid having a solid phase at a temperature of 30 ° C. or lower and having a melting point of 40 ° C. to 150 ° C. 27. 28. The method of claim 27, wherein the solid lipid is a C10-22 saturated fatty acid and its ester compound and its alcohol compound, a mono- or di-glyceride compound having a C10-22 saturated fatty acid group, a hydrocarbon having 16 or more carbon atoms A method for producing amorphous particles of an active substance, characterized in that it is a mixture of one or two or more compounds selected from the group consisting of fatty acid reducing compounds of 10 to 22 triglyceride compounds. The group according to any one of claims 19 to 25, wherein the mixture prepared in step (1) is made of a synthetic surfactant, a natural surfactant, a lipid, a polymer, a monosaccharide, a polysaccharide, a dietary fiber, a gum and a protein. Method for producing amorphous particles of the active material, characterized in that it further comprises one or more materials selected from. 26. The method of claim 20, wherein the surfactant is at least one selected from the group consisting of synthetic surfactants, natural surfactants, lipids and polymers. 26. The active substance according to any one of claims 21, 22 and 25, wherein the anti-agglomeration agent other than the surfactant is selected from the group consisting of monosaccharides, polysaccharides, dietary fibers, gums and proteins. Method for producing amorphous particles. The method for producing amorphous particles of the active material according to any one of claims 19 to 25, wherein a cosolvent is further used in the step (1). 33. The method of claim 32, wherein the cosolvent is an alcohol having 2 to 6 carbon atoms. The activity according to any one of claims 19 to 25, wherein the temperature in the reactor in step (2) is a temperature below the melting point of the solid lipid contained in the mixture obtained in step (1). A method for producing amorphous particles of a material. The method according to any one of claims 19 to 25, wherein the temperature in the reactor in the step (2) is 20 to 40 ° C. 26. The method according to any one of claims 19 to 25, wherein in step (2), a supercritical fluid gas is added to a mixture comprising the active substance and the solid lipid to remove the solid lipid under 70 to 400 atmospheres. Method for producing amorphous particles of the active material, characterized in that.